Presentation of Qa-1 restricted peptides during homeostasis and viral infection

Qa-1 限制性肽在稳态和病毒感染期间的呈现

• 批准号: 10369722
• 负责人: LAURENT COSCOY
• 金额: $ 57.48万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369722
• 关键词: Affinity; Age; Agonist; Aminopeptidase; Antigen Presentation; Antigen Presentation Pathway; Automobile Driving; CD8-Positive T-Lymphocytes; CD94 Antigen; Cells; Characteristics; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Down-Regulation; Family; Generations; Germ Lines; Goals; HIV vaccine; Homeostasis; Human; Immune; Immune Evasion; In Vitro; Infection; KLRD1 gene; Lead; Ligands; Light; Macaca; Mediating; Modeling; Mouse Strains; Mus; Natural Killer Cells; Peptide Leader Sequences; Peptide/MHC Complex; Peptides; Phenotype; Play; Positioning Attribute; Principal Investigator; Proteins; Qa-1 Antigen; Role; SIV Vaccines; Signal Transduction; Splenocyte; Stress; Structure of thymic cortex; Structure of thymic medulla; T cell response; T-Lymphocyte; Techniques; Testing; Thymus Gland; Tissues; Transgenic Mice; Tumor Immunity; Up-Regulation; Vaccine Design; Vaccines; Viral; Virus Diseases; Wild Type Mouse; antigen processing; base; cell transformation; cell type; cooking; cross reactivity; immunoregulation; in vivo; insight; interest; member; pathogen; programs; receptor; response; vector

Program Director/Principal Investigator (Robey, Ellen, A): Abstract: Mouse Qa-1 is a member of the conserved MHC-E family of non-classical MHC-1 molecules (MHC1b). In most cells, MHC-E presents peptides derived from the leader sequences of classical (MHC1a) molecules, and regulates the function of NK cells through the germ-line encoded receptor CD94/NKG2. MHC-E molecules can also present self and pathogen-derived peptides to CD8 T cells. The signals that lead to presentation of alternative peptides by MHC-E, and the functions of the responding CD8 T cells remain poorly understood. Recently, studies of a highly effective HIV vaccine based on a CMV vector revealed a prominent MHC-E restricted CD8 T cell response, raising new interest in understanding the presentation mechanisms and in vivo functions of MHC-E. Together with our collaborators, we have been investigating a Qa-1-restricted T cell response to cells lacking the ER aminopeptidase associated with antigen processing (ERAAP ko) (Nagarajan et al., 2012). The responding CD8 T cells recognize a 9-mer peptide derived from a self-protein (FL9 from FAM49) presented by Qa-1(b) (called QFL T cells). QFL T cells use an invariant TCR a, and have characteristics of both conventional and non-conventional CD8 T cells. Our preliminary data indicate that QFL T cells encounter high affinity Qa-1 restricted ligands at steady state and during viral infection. We propose to use a newly generated TCR transgenic mouse strain to probe the in vivo generation of Qa-1 restricted ligands for QFL T cells in both steady state and during viral infection. In Aim 1, we will identify the pMHC ligands involved in positive and agonist selection of QFL T cells, and will identify the thymic cell types that present the ligands. In Aim 2, we will identify the ligand(s) that drive the homeostatic expansion of QFL T cells, and will determine when, in what tissue, and by what cell type(s) they are presented. In Aim 3, we will determine the mechanisms that lead to priming of QFL T cells during MCMV infection, and will test whether QFL T cells induced during MCMV infection can kill infected cells and provide immune protection. Our results will shed new light on how MHC-E presentation regulates T cell responses, with important implications for vaccine design. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

项目负责人/主要研究者（Robey，Ellen，A）： 摘要： 小鼠Qa-1是非经典MHC-1分子（MHC 1b）保守MHC-E家族的成员。在 在大多数细胞中，MHC-E呈递源自经典（MHC 1a）分子前导序列的肽， 通过生殖系编码的受体CD 94/NKG 2调节NK细胞的功能。MHC-E分子可以 还将自身和病原体衍生的肽呈递给CD 8 T细胞。导致呈现的信号 MHC-E的替代肽，和响应的CD 8 T细胞的功能仍然知之甚少。 最近，基于CMV载体的高效HIV疫苗的研究揭示了突出的MHC-E 限制性CD 8 T细胞应答，引起了人们对理解呈递机制和体内 MHC-E的功能 与我们的合作者一起，我们一直在研究Qa-1限制性T细胞对细胞的反应， 缺乏与抗原加工相关的ER氨肽酶（ERAAPko）（Nagarajan等，2012年）。的 响应性CD 8 T细胞识别由以下呈递的源自自身蛋白的9聚体肽（来自FAM 49的FL 9）： Qa-1（B）（称为QFL T细胞）。QFL T细胞使用不变的TCR α，并且具有两者的特征。 常规和非常规CD 8 T细胞。我们的初步数据表明，QFL T细胞遇到高水平的免疫应答。 稳定状态下和病毒感染期间的亲和力Qa-1限制性配体。我们建议使用新生成的 TCR转基因小鼠品系，以探测在两种细胞中QFL T细胞的Qa-1限制性配体的体内产生。 稳定状态和病毒感染期间。在目标1中，我们将鉴定参与阳性和阴性反应的pMHC配体。 QFL T细胞的激动剂选择，并将鉴定呈递配体的胸腺细胞类型。在目标2中，我们将 识别驱动QFL T细胞稳态扩增的配体，并将确定何时、以何种方式 组织，以及它们被呈递的细胞类型。在目标3中，我们将确定导致 在MCMV感染过程中引发QFL T细胞，并将测试在MCMV感染过程中是否诱导QFL T细胞 感染可以杀死受感染的细胞并提供免疫保护。 我们的研究结果将为MHC-E呈递如何调节T细胞应答提供新的线索， 对疫苗设计的影响。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码